crossing96/oncoscreening huggingface dataset:
Impact of preoperative chemotherapy on pathologic nodal status in muscle-invasive bladder cancer: optimal lymphadenectomy in the preoperative chemotherapy era.	PURPOSE: To investigate the impact of preoperative chemotherapy (pCTX) on pathologic nodal (pN) status and evaluate the optimal lymphadenectomy method according to clinical nodal (cN) status in patients with muscle-invasive bladder cancer who received pCTX. MATERIALS AND METHODS: We retrospectively reviewed 449 patients with muscle-invasive bladder cancer who underwent radical cystectomy. Among them, 139 (31.0%) received pCTX. We analyzed overall survival among three groups (cN-pCTX-, cN-pCTX+, and cN+pCTX+); the impact of lymphadenectomy extent according to the history of pCTX in cN- patients (n = 393); and the pN status which includes number of positive lymph nodes, and lymph node density in cN- patients who underwent extended lymphadenectomy (n = 222). RESULTS: Overall survival was significantly dependent on cN status, and pCTX had no survival advantage although it decreased the percentage of pN+ patients and the number of positive lymph nodes in cN- patients. Lymph node density showed a significant prognostic effect on overall survival in Cox regression analysis both in cN- and cN+ patients. In cN- patients, there was no significant survival difference according to lymphadenectomy extent regardless of receiving pCTX. CONCLUSIONS: pCTX can control micrometastases but not overt metastases, despite decreasing the number of positive lymph nodes in patients with muscle-invasive bladder cancer. Although extended lymphadenectomy is a reasonable diagnostic strategy in the pCTX era, standard dissection is as therapeutic as extended dissection in patients with cN- disease.	bladder
RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics.	Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.	bladder
Poor clinical guideline adherence and inappropriate testing for incident lower urinary tract symptoms associated with benign prostatic hyperplasia.	BACKGROUND: The American Urological Association makes recommendations for evaluation and testing for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) to help primary care providers and specialists identify LUTS/BPH and harmful related conditions including urinary retention and prostate or bladder cancer. Our understanding of provider adherence to these Guidelines is limited to single-site or nonrepresentative settings. METHODS: We analyzed two insurance claims databases: the Optum(®) de-identified Clinformatics(®) Data Mart database for privately insured males aged 40-64 years (N ≈ 1,650,900 annually) and the Medicare 5% Sample for males aged ≥65 years (N ≈ 546,000 annually). We calculated the annual prevalence of LUTS/BPH and comorbid bladder cancer and bladder stones from 2004 to 2013. We additionally examined LUTS/BPH incidence and adherence to testing guidelines in a cohort of men newly diagnosed with LUTS/BPH in 2009. RESULTS: While LUTS/BPH prevalence and incidence increased with increasing age, evaluation testing became less common. Urinalysis was the most common testing type but was performed in <60% of incident patients. Serum prostate-specific antigen (PSA) was the second most common test across age groups (range: 15-34%). Prevalence of comorbid bladder cancer (range: 0-4%), but not bladder stones (range: 1-2%), increased with increasing age. CONCLUSIONS: Although older men were at greater risk of LUTS/BPH than younger men, they were less likely to undergo testing at diagnosis. Recommended testing with urinalysis was poor despite higher prevalence of bladder cancer in older men and a standard recommendation for urinalysis since 1994. Providers should be more cognizant of AUA Guidelines when assessing LUTS/BPH patients.	bladder
Silencing circ‑BIRC6 inhibits the proliferation, invasion, migration and epithelial‑mesenchymal transition of bladder cancer cells by targeting the miR‑495‑3p/XBP1 signaling axis.	Circular RNAs (circRNAs) regulate gene expression by acting as a 'sponge' for microRNAs (miRs) and play crucial roles in tumorigenesis, including in bladder cancer (BC). circRNA‑baculoviral IAP repeat‑containing 6 (circ‑BIRC6) has been reported to participate in the pathogenesis of several cancer types. The present study aimed to elucidate the roles and potential mechanisms of circ‑BIRC6 in the progression of BC. circ‑BIRC6 expression levels in BC cell lines were determined using reverse transcription‑quantitative PCR. Following circ‑BIRC6 knockdown, cell proliferation, invasion and migration were detected using Cell Counting Kit‑8, colony formation, Transwell and wound healing assays, respectively. Western blotting was also conducted to evaluate the expression levels of X‑box binding protein 1 (XBP1) and epithelial‑mesenchymal transition (EMT)‑associated proteins. In addition, rescue experiments were performed using by transfecting a miR‑495‑3p inhibitor into T24 cells following circ‑BIRC6 knockdown. The interactions between circ‑BIRC6, miR‑495‑3p and XBP1 was verified using dual luciferase reporter assays. Moreover, T24 cells with circ‑BIRC6 knockdown and miR‑495‑3p inhibitor transfection were used for the tumor‑bearing experiment. Tumor growth was observed and Ki‑67 expression was determined using immunohistochemistry. The results demonstrated that circ‑BIRC6 expression was upregulated in BC cell lines. Moreover, circ‑BIRC6 knockdown notably attenuated the proliferation, invasion, migration and EMT of BC cells, which was blocked by the miR‑495‑3p inhibitor. It was also identified that circ‑BIRC6 sponged miR‑495‑3p to regulate XBP1 expression. In addition, results from the xenograft experiments indicated that the knockdown of circ‑BIRC6 and miR‑495‑3p expression significantly inhibited tumor growth. It was also found that the expression levels of XBP1, Ki‑67 and EMT‑associated proteins in tumor tissues of the co‑transfection group were markedly restored compared with the circ‑BIRC6 knockdown group. In conclusion, these findings demonstrated that circ‑BIRC6 knockdown suppressed BC tumorigenesis and progression via regulation of the miR‑495‑3p/XBP1 signaling axis, offering a promising therapeutic target for the treatment of BC.	bladder
MAFG-AS1/MAFG positive feedback loop contributes to cisplatin resistance in bladder urothelial carcinoma through antagonistic ferroptosis.	Though promoting ferroptosis can reduce cisplatin resistance in tumor cells, ferroptosis and cisplatin resistance in bladder urothelial carcinoma (BUC) following long non-coding RNAs (lncRNAs) is largely unknown. Here, we found the highly expressed lncRNA MAF transcription factor G antisense RNA 1 (MAFG-AS1) in BUC, and its inhibition increased the sensitivity of BUC cells to cisplatin by promoting ferroptosis. Mechanically, binding to iron chaperone poly(rC)-binding protein 2 (PCBP2) facilitated the recruitments of MAFG-AS1 to deubiquitinase ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5), thus stabilizing PCBP2 protein itself. Then PCBP2 was confirmed to interact with ferroportin 1 (FPN1), an iron export protein, leading to inhibition of ferroptosis. Moreover, the expression of MAFG-AS1 was regulated by the transcriptional factor MAFG. Interestingly, MAFG-AS1 stimulated MAFG transcription by recruiting histone acetyltransferase p300 (EP300) to promote the histone 3 at lysine 27 (H3K27ac) at genomic locus of MAFG, forming a MAFG-AS1/MAFG positive feedback loop. In patient samples, higher expression of MAFG-AS1 and MAFG in BUC tissues was significantly correlated with T status and N status, such that MAFG-AS1, MAFG, and the combination of the two were independent prognostic indicators and chemotherapy sensitivity predictive biomarkers for BUC patients. These findings suggest that inhibition of MAFG-AS1 and MAFG can increase the sensitivity of BUC cells to cisplatin through promoting ferroptosis, indicating the novel chemotherapy sensitivity biomarkers and therapeutic target for BUC.	bladder
Long non-coding RNAs as new players in bladder cancer: Lessons from pre-clinical and clinical studies.	The clinical management of bladder cancer (BC) has become an increasing challenge due to high incidence rate of BC, malignant behavior of cancer cells and drug resistance. The non-coding RNAs are considered as key factors involved in BC progression. The long non-coding RNAs (lncRNAs) are RNA molecules and do not encode proteins. They have more than 200 nucleotides in length and affect gene expression at epigenetic, transcriptional and post-transcriptional phases. The lncRNAs demonstrate abnormal expression in BC cells and tissues. The present aims to identifying lncRNAs with tumor-suppressor and tumor-promoting roles, and evaluating their roles as regulatory of growth and migration. Apoptosis, glycolysis and EMT are tightly regulated by lncRNAs in BC. Response of BC cells to cisplatin, doxorubicin and gemcitabine chemotherapy is modulated by lncRNAs. LncRNAs regulate immune cell infiltration in tumor microenvironment and affect response of BC cells to immunotherapy. Besides, lncRNAs are able to regulate microRNAs, STAT3, Wnt, PTEN and PI3K/Akt pathways in affecting both proliferation and migration of BC cells. Noteworthy, anti-tumor compounds and genetic tools such as siRNA, shRNA and CRISPR/Cas systems can regulate lncRNA expression in BC. Finally, lncRNAs and exosomal lncRNAs can be considered as potential diagnostic and prognostic tools in BC.	bladder
TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer.	Bladder cancer (BC) has a 70% telomerase reverse transcriptase (TERT or hTERT in humans) promoter mutation prevalence, commonly at -124 base pairs, and this is associated with increased hTERT expression and poor patient prognosis. We inserted a green fluorescent protein (GFP) tag in the mutant hTERT promoter allele to create BC cells expressing an hTERT-GFP fusion protein. These cells were used in a fluorescence-activated cell sorting-based pooled CRISPR-Cas9 Kinome knockout genetic screen to identify tripartite motif containing 28 (TRIM28) and TRIM24 as regulators of hTERT expression. TRIM28 activates, while TRIM24 suppresses, hTERT transcription from the mutated promoter allele. TRIM28 is recruited to the mutant promoter where it interacts with TRIM24, which inhibits its activity. Phosphorylation of TRIM28 through the mTOR complex 1 (mTORC1) releases it from TRIM24 and induces hTERT transcription. TRIM28 expression promotes in vitro and in vivo BC cell growth and stratifies BC patient outcome. mTORC1 inhibition with rapamycin analog Ridaforolimus suppresses TRIM28 phosphorylation, hTERT expression, and cell viability. This study may lead to hTERT-directed cancer therapies with reduced effects on normal progenitor cells.	bladder
Usefulness of advanced monoenergetic reconstruction technique in dual-energy computed tomography for detecting bladder cancer.	PURPOSE: Detecting bladder cancer (BC) in routine CT images is important but is sometimes difficult when cancer is small. We evaluated the ability of 40-keV advanced monoenergetic images to depict BC. MATERIALS AND METHODS: Fifty-two patients with a median age of 74 years (range 45-92) who were diagnosed as BC with transurethral resection or cystectomy, were included. They were examined with contrast-enhanced dual-energy CT (DE-CT) and advanced virtual monoenergetic images (40 keV) were reconstructed. For evaluating depictability of BC on 40-keV or virtual-120-kVp images, the difference in CT number between the cancer and bladder wall (BC-BW value) were calculated. We also subjectively assessed depictability of BC in virtual-120-kVp and 40-keV images using a 4-grade Likert scale (3: clear, 0: not visualized). RESULTS: In 42 of 52 patients, BC-BW values could be calculated because BC was detected on CT images. The mean BC-BW value at 40 keV was significantly higher than that of virtual 120 kVp [80.5 ± 54 (SD) vs. 11.4 ± 12.5 HU, P < 0.01]. Average scores of subjective evaluations in the virtual-120-kVp and 40-keV images were 1.7 ± 1.2 and 2.1 ± 1.2, respectively (P < 0.001). CONCLUSION: The advanced monoenergetic reconstruction technique reconstructed using DE-CT image is useful to depict BC.	bladder
PD-L1 (SP142) testing is concordant between Benchmark Ultra and Bond-III stainers.	BACKGROUND: Atezolizumab is an inhibitor of programmed death-ligand 1 (PD-L1), used to treat advanced or metastatic bladder cancer, and in trials for non-invasive disease. In order to be eligible for treatment, patients require a PD-L1 immune cell score ≥ 5%, using the Ventana SP142 PD-L1 assay. Many laboratories do not have access to the required Ventana Benchmark Ultra stainer, and it is unclear if the assay performs similarly on other stainers. In this study, we compare SP142 assay results between Ventana Benchmark Ultra and Leica Bond-III stainers. METHODS: Serial sections of 90 samples of transurethral bladder resections (comprising 51 pTaHG, 8 pTis, 18 pT1, 10 pT2 tumors) were stained using the SP142 PD-L1 antibody on Ventana Benchmark Ultra and Leica Bond-III stainers, manually scored, and compared using accuracy and Cohen's kappa measures. RESULTS: Both devices yielded highly concordant PD-L1 immune cell scores (accuracy 0.84, Cohen's κ 0.732). Moreover, we found similar tumor cell (TC) PD-L1 scores using both stainers, and a trend towards greater TC scores in pT2 stage samples (p = 0.05). CONCLUSION: This study is the first to compare the SP142 antibody in bladder cancer on two different stainers. Our results indicate that both Benchmark Ultra and Bond-III stainers yield highly concordant results using the SP142 PD-L1 antibody.	bladder
Rab6c is a new target of miR‑218 that can promote the progression of bladder cancer.	Bladder cancer has high morbidity and mortality rates among the male genitourinary system tumor types. MicroRNA‑218 (miR‑218) is associated with the development of a variety of cancer types, including bladder cancer. Rab6c is a member of the Rab family and is involved in drug resistance in MCF7 cells. The aim of the present study was to clarify the relationship between Rab6c and miR‑218 in bladder cancer cell lines. In this study, the expression levels of miR‑218 and Rab6c were evaluated via reverse transcription‑quantitative PCR and western blotting, respectively. The association between Rab6c and miR‑218 was recognized via TargetScan analysis and dual luciferase reporter gene detection. Cell proliferation was analyzed using Cell Counting Kit‑8 and colony formation assays, and the invasive ability was measured via Transwell assays. Rab6c was highly expressed in bladder cancer, while miR‑218 had abnormally low expression in bladder cancer. In addition, there was a mutual regulation between Rab6c and miR‑218 in bladder cancer. It was found that overexpression of Rab6c significantly enhanced the proliferation, colony formation and invasion of T24 and EJ cells. Furthermore, miR‑218 overexpression blocked the promoting effects of Rab6c on the malignant behavior of bladder cancer cells. Thus, Rab6c promotes the proliferation and invasion of bladder cancer cells, while miR‑218 has the opposite effect, which may provide a novel insight for the treatment of bladder cancer.	bladder
Development of Skin Rash Predicts Outcome of Anti-PD-1- and Anti-CTLA4-Based Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer or Squamous Cell Carcinoma of the Head and Neck: A Single-Center Analysis.	OBJECTIVE: We report the spectrum of immune-related adverse effects (irAEs) and outcome observed in a single-center cohort of 100 patients treated with immune checkpoint inhibitors in a routine clinical setting. METHODS: Tumor entities included non-small cell lung cancer (n = 28), head and neck squamous cell carcinoma (n = 28), urothelial carcinoma (n = 7), and others (n = 37). RESULTS: irAEs were documented in 49% of cases analyzed, and the most frequent manifestation consisted of immune-mediated skin rash (28%), colitis (9%), pneumonitis (8%), hypothyroidism (7%), or hepatitis (6%). Skin rash correlated with improved progression-free survival. CONCLUSION: Development of immune-related skin rash was found to correlate with favorable outcome, suggesting its practical feasibility as a potential predictive surrogate marker.	bladder
Application of a multiplex urinalysis test for the prediction of intravesical BCG treatment response: A pilot study.	BACKGROUND: Intravesical Bacillus Calmette-Guerin (BCG), a live attenuated tuberculosis vaccine that acts as a non-specific immune system stimulant, is the most effective adjuvant treatment for patients with intermediate or high-risk non-muscle-invasive bladder cancer (NMIBC). However, to date, there are no reliable tests that are predictive of BCG treatment response. In this study, we evaluated the performance of OncuriaTM, a bladder cancer detection test, to predict response to intravesical BCG. METHODS: OncuriaTM data was evaluated in voided urine samples obtained from a prospectively collected cohort of 64 subjects with intermediate or high risk NMIBC prior to treatment with intravesical BCG. The OncuriaTM test, which measures 10 cancer-associated biomarkers was performed in an independent clinical laboratory. The ability of the test to identify those patients in whom BCG is ineffective against tumor recurrence was tested. Predictive models were derived using supervised learning and cross-validation analyses. Model performance was assessed using ROC curves. RESULTS: Pre-treatment urinary concentrations of MMP9, VEGFA, CA9, SDC1, PAI1, APOE, A1AT, ANG and MMP10 were increased in patients who developed disease recurrence. A combinatorial predictive model of treatment outcome achieved an AUROC 0.89 [95% CI: 0.80-0.99], outperforming any single biomarker, with a test sensitivity of 81.8% and a specificity of 84.9%. Hazard ratio analysis revealed that patients with higher urinary levels of ANG, CA9 and MMP10 had a significantly higher risk of disease recurrence. CONCLUSIONS: Monitoring the urinary levels of a cancer-associated biomarker panel enabled the discrimination of patients who did not respond to intravesical BCG therapy. With further study, the multiplex OncuriaTM test may be applicable for the clinical evaluation of bladder cancer patients considering intravesical BCG treatment.	bladder
MOLECULAR CHARACTERISTICS OF THE HETEROGENEITY OF NON-INVASIVE PAPILLARY UROTHELIAL CARCINOMAS AND THE MARKERS OF THEIR RECURRENCE.	Urothelial carcinoma represents the most common type of bladder cancer (>90%) and is the most frequent malignancy of the urinary tract. Most of the urothelial carcinomas are non-invasive at the time of diagnosis, however they are characterised with the risk of recurrence after surgical treatment. The aim of our study was to investigate the characteristics of tumor heterogeneity and markers of its progression in urothelial papillary carcinomas. Study included following groups: normal urothelial epithelium, urothelial papilloma, urothelial neoplasms with low malignant potential (PUNLM), non-invasive low grade papillary urothelial carcinomas (LGPUC) and non-invasive high grade papillary urothelial carcinomas (HGPUC). In addition, study included relapsed cases of non-invasive LGPUC and HGPUC. Nuclear features and mitotic counts was assessed using digital pathology software QuPath in standard H&E stained specimens. In addition, the presence of mitosis was detected as PHH3 labelled cells by immunohistochemistry. Proliferation was measured as Ki67 labelling index by immunohistochemistry. Tumor heterogeneity was investigated by the differential expression pattern of CK5, CK7 and CK20 by immunohistochemistry. Study results showed, that Nuclear features, as well as the number of mitosis, proliferation index and intratumoral heterogeneity significantly correlate with the presence of higher grade non-invasive urothelial lesions. In addition, it is possible to distinguish two major groups of non-invasive LGPUC and HGPUC, based on nuclear and phenotypic heterogeneity and mitotic and proliferative activity, I group which is characterised with higher intratumoral heterogeneity, higher mitotic count and higher proliferative activity, represents the high risk group of non-invasive LGPUC and HGPUC recurrence.	bladder
Development of a multiplex immuno-oncology biomarker and digital pathology workflow for assessment of urothelial carcinoma.	BACKGROUND: Immune checkpoint inhibitors (ICI) therapies have demonstrated significant benefit in the treatment of many tumors including high grade urothelial cancer (HGUC) of the bladder. However, variability in patients' clinical responses highlights the need for biomarkers to aid patient stratification. ICI relies on an intact host immune response. In this context, we hypothesize that key players in the antitumor immune response such as markers of activated cytotoxic T lymphocytes (CD8, granzyme-B) and immune suppression (FOXP3) may help to identify patients who will derive the greatest therapeutic benefit from ICI. A major obstacle for deployment of such a strategy is the limited quantities of tumor-derived biopsy material. Therefore, in this technical study, we develop a multiplex biomarker with digital workflow. We explored the (1) concordance of conventional single stain results using digital image analysis, and (2) agreement between digital scoring versus manual analysis. METHODS: (1) For concordance study of single and multiplex stains, triplicate core tissue microarrays of 207 muscle invasive, HGUC of bladder had sequential 4-micron sections cut and stained with CD8, FOXP3 and granzyme-B. An inhouse developed tri-chromogen multiplex immunohistochemistry (m-IHC) assay consisting of CD8 (green), granzyme B (brown), and FOXP3 (red) was used to stain the next sequential tissue section. (2) Agreement between manual and digital analysis was performed on 19 whole slide sections of HGUC cystectomy specimens. All slides were scanned using Aperio ScanScope AT Digital Scanner at 40X. Quantitative digital image analysis was performed using QuPath version 0.2.3 open-source software. Scores from triplicate cores were averaged for each HGUC specimen for each marker. Intraclass correlation coefficients were used to compare percent positive cells between the single- and multi-plex assays. Lin's concordance correlation coefficients were used for manual versus digital analysis. RESULTS AND CONCLUSIONS: m-IHC offers significant advantages in characterizing the host immune microenvironment particularly in limited biopsy tissue material. Utilizing a digital image workflow resulted in significant concordance between m-IHC and individual single stains (p < 0.001 for all assessments). Moderate to good agreements were achieved between manual and digital scoring. Our technical work demonstrated potential uses of multiplex marker in assessing the host immune status and could be used in conjunction with PD-L1 as a predictor of response to ICI therapy.	bladder